rs773670891

Positions:

• chr1-25802114-CTGAG-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_020451.3(SELENON):​c.402_403+2del variant causes a splice donor, coding sequence change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 274,290 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: SELENON NM_020451.3 splice_donor, coding_sequence
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 0.598

Genes affected

SELENON (HGNC:15999): (selenoprotein N) This gene encodes a glycoprotein that is localized in the endoplasmic reticulum. It plays an important role in cell protection against oxidative stress, and in the regulation of redox-related calcium homeostasis. Mutations in this gene are associated with early onset muscle disorders, referred to as SEPN1-related myopathy. SEPN1-related myopathy consists of 4 autosomal recessive disorders, originally thought to be separate entities: rigid spine muscular dystrophy (RSMD1), the classical form of multiminicore disease, desmin related myopathy with Mallory-body like inclusions, and congenital fiber-type disproportion (CFTD). This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec). Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. A second stop-codon redefinition element (SRE) adjacent to the UGA codon has been identified in this gene (PMID:15791204). SRE is a phylogenetically conserved stem-loop structure that stimulates readthrough at the UGA codon, and augments the Sec insertion efficiency by SECIS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.056965593 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-25802114-CTGAG-C is Pathogenic according to our data. Variant chr1-25802114-CTGAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461633.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, Pathogenic=1}. Variant chr1-25802114-CTGAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SELENON	NM_020451.3	c.402_403+2del		splice_donor_variant, coding_sequence_variant	3/13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.301+956_301+959del		intron_variant			NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.402_403+2del		splice_donor_variant, coding_sequence_variant	3/13	1	NM_020451.3	ENSP00000355141
SELENON	ENST00000354177.9	c.301+956_301+959del		intron_variant		5		ENSP00000346109
SELENON	ENST00000374315.1	c.301+956_301+959del		intron_variant		5		ENSP00000363434	P1
SELENON	ENST00000494537.2	c.301+956_301+959del		intron_variant, NMD_transcript_variant		3		ENSP00000508308

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000991

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 4 AN: 35924 Hom.: 0 AF XY: 0.0000501 AC XY: 1 AN XY: 19970

Gnomad AFR exome AF: 0.00264

Gnomad AMR exome AF: 0.000137

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000655 AC: 8 AN: 122162 Hom.: 0 AF XY: 0.0000282 AC XY: 2 AN XY: 70868

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.000104

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000467

Gnomad4 OTH exome AF: 0.000173

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74368

Gnomad4 AFR AF: 0.000988

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.000366

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2024	Variant summary: SELENON c.402_403+2delGAGT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of SELENON function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 274290 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SELENON causing Eichsfeld Type Congenital Muscular Dystrophy (0.0002 vs 0.0011), allowing no conclusion about variant significance. c.402_403+2delGAGT has been reported in the literature in the heterozygous state in a sudden death of a young individual (Salfati_2019). This report does not provide unequivocal conclusions about association of the variant with Eichsfeld Type Congenital Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 461633). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This variant results in the deletion of part of exon 3 (c.402_403+2del) of the SELENON gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436). This variant is present in population databases (rs773670891, gnomAD 0.1%). This variant has been observed in individual(s) with clinical features of SELENON-related conditions (PMID: 31847883). ClinVar contains an entry for this variant (Variation ID: 461633). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 31, 2022	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The c.402_403+2del variant in SELENON has not been previously reported in the literature in individuals with SELENON-RM but has been identified in 0.1% (13/9840) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs773670891). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 461633) and has been interpreted as likely pathogenic by Invitae, GeneDx, and PerkinElmer Genomics. Conservation and expression data indicate that this exon might not be biologically relevant for this disease, and therefore this variant is not expected to result in loss of function of SELENON. In summary, the clinical significance of the c.402_403+2del variant is uncertain. ACMG/AMP Criteria applied: none (Richards 2015). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 2021

Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Deletions involving coding exons of this gene are a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21131290, 21670436) -

Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.41		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs773670891; hg19: chr1-26128605;